In order to elucidate a combination of genetic alterations that drive tobacco carcinogenesis we have explored a unique model system and analytical method for an unbiased qualitative and quantitative assessment of gene-gene and gene-environment interactions. The objective of this case control study was to assess genetic predisposition in a biologically enriched clinical model system of tobacco related cancers (TRC), occurring as Multiple Primary Neoplasms (MPN).

Multiple primary neoplasms in surviving cancer patients are relatively common, with an increasing incidence. Their impact on survival has not been clearly defined.

Comprehensive studies in second primary cancer (SPC) after the initial primary human papillomavirus (HPV)-related cancer still remain warranted. We aimed to analyze the incidence and risk factors of SPC after HPV-related cancer. We identified 86 790 patients diagnosed with initial primary HPV-related cancer between 1973 and 2010 in the SEER database. Standardized incidence ratio (SIR) and cumulative incidence were calculated to assess the risk of SPC after HPV-related cancer. The SIR of SPC after HPV-related cancer was 1.60 (95% confidence interval [CI], 1.55-1.65) for male and 1.25 (95% CI, 1.22-1.28) for female. SIR of second primary HPV-related cancer (7.39 [95% CI, 6.26-8.68] male and 4.35 [95% CI, 4.04-4.67] female) was significantly higher than that of HPV-unrelated cancer (1.54 [95% CI, 1.49-1.60] male and 1.16 [95% CI, 1.13-1.19] female). The 5-year cumulative incidence of SPC was 7.22% (95% CI, 6.89-7.55%) for male and 3.72% (95% CI, 3.58-3.88%) for female. Risk factors for SPC included being married and having initial primary cancer (IPC) diagnosed at earlier stage for both genders, and IPC diagnosed at older age as well as surgery performed for female. Patients diagnosed with HPV-related cancer are more likely to develop another primary cancer, compared with the age-specific reference population.

Patients with melanoma have an increased risk of having other neoplasms, and particularly other melanomas and non-melanoma skin cancers. The study aimed to describe multiple primary melanomas in a large medical university centre from Romania (Cluj-Napoca) from 2004 to 2020. Out of 699 patients with melanoma included in the study, 26 (3.71%) developed multiple tumours. The 26 patients developed a total of 59 melanomas, corresponding to a mean of 2.3 melanomas per patient. The site and histological subtype of the first and second melanomas were not consistent. The proportion of subsequent melanomas that were in situ (51.5%) or thin melanomas (<1 mm, 24.2%) was higher compared with first melanomas (7.7%, respectively 11.5%). The median and mean time to diagnosis was 2.75 months, respectively, 28.09 months. In total, 76.92% of second melanomas were detected within three years, but we were able to document a subsequent melanoma more than ten years after the first diagnosis. The study highlights the importance of follow-up in patients diagnosed with melanoma, not only in the first years after the primary diagnoses but for the entire life.

Large population-based studies of risk factor for lung metastases at the presentation with primary osseous neoplasms are lacking and necessary. We aim to examine potential risk factors of lung metastases at presentation with primary osseous neoplasms using Surveillance, Epidemiology, and End Results (SEER) database tool.

Although the concept of "myeloid neoplasm continuum" has long been proposed, few comparative genomics studies directly tested this hypothesis. Here we report a multi-modal data analysis of 730 consecutive newly diagnosed patients with primary myeloid neoplasm, along with 462 lymphoid neoplasm cases serving as the outgroup. Our study identified a "Pan-Myeloid Axis" along which patients, genes, and phenotypic features were all aligned in sequential order. Utilizing relational information of gene mutations along the Pan-Myeloid Axis improved prognostic accuracy for complete remission and overall survival in adult patients of de novo acute myeloid leukemia and for complete remission in adult patients of myelodysplastic syndromes with excess blasts. We submit that better understanding of the myeloid neoplasm continuum might shed light on how treatment should be tailored to individual diseases.

CD99(MIC2) is a widely expressed cell surface glycoprotein and functions as a tumor suppressor involved in downregulation of SRC family of tyrosine kinase. CD99 expression is tightly regulated through B-cell development. The principal aims of this study were to investigate the clinical utility of CD99 expression (i) in distinguishing normal plasma cells from primary plasma cell neoplasms; (ii) in detection of minimal residual disease in primary plasma cell neoplasms; and (iii) in distinguishing plasma cell component of B-cell lymphomas from primary plasma cell neoplasms. We analyzed expression of CD99 by flow cytometry and immunohistochemistry in lymph nodes, peripheral blood, and bone marrow samples. CD99 showed stage-specific expression with highest expression seen in precursor B and plasma cells. In contrast to the uniform bright expression on normal plasma cells, CD99 expression on neoplastic plasma cells was lost in 39 out of 56 (69.6%) cases. Furthermore, 8 out of 56 samples (14%) showed visibly (>10-fold) reduced CD99 expression. Overall, CD99 expression was informative (absent or visibly dimmer than normal) in 84% of primary plasma cell neoplasm. In the context of minimal residual disease detection, CD99 showed superior utility in separating normal and abnormal plasma cells over currently established antigens CD117, CD81, and CD27 by principal component analysis. Preservation of CD99 expression was strongly associated with cyclin D1 translocation in myeloma (p < 0.05). B-cell lymphomas with plasma cell component could be distinguished from myeloma by CD99 expression. In summary, we established that tumor suppressor CD99 is markedly downregulated in multiple myeloma. The loss is highly specific for identification of abnormal cells in primary plasma cell neoplasms, and can be exploited for diagnostic purposes. The role of CD99 in myeloma pathogenesis requires further investigation.

This study aimed to evaluate the risk factors of developing second primary malignancies (SPMs) among patients with pancreatic neuroendocrine neoplasms (pNENs) and the prognosis of pNENs patients with SPMs (pSPMs) using data from the Surveillance, Epidemiology, and End Results (SEER) database.

Several lines of research suggest that Bcl-xL-mediated anti-apoptotic effects may contribute to the pathogenesis of myeloproliferative neoplasms driven by JAK2V617F and serve as therapeutic target. Here, we used a knock-in JAK2V617F mouse model and confirmed that Bcl-xL was overexpressed in erythroid progenitors. The myeloproliferative neoplasm (MPN)-induced phenotype in the peripheral blood by conditional knock-in of JAK2V617F was abrogated by conditional knockout of Bcl2l1, which presented anemia and thrombocytopenia independently of JAK2 mutation status. Mx1-Cre Jak2V617W/VF /Bcl2l1f/f mice presented persistent splenomegaly as a result of extramedullary hematopoiesis and pro-apoptotic stimuli in terminally differentiated erythroid progenitors. The pan-BH3 mimetic inhibitor obatoclax showed superior cytotoxicity in JAK2V617F cell models, and reduced clonogenic capacity in ex vivo assay using Vav-Cre Jak2V617F bone marrow cells. Both ruxolitinib and obatoclax significantly reduced spleen weights in a murine Jak2V617F MPN model but did not show additive effect. The tumor burden reduction was observed with either ruxolitinib or obatoclax in terminal differentiation stage neoplastic cells but not in myeloid-erythroid precursors. Therefore, disrupting the BCL2 balance is not sufficient to treat MPN at the stem cell level, but it is certainly an additional option for controlling the critical myeloid expansion of the disease.

Neuroendocrine neoplasms of the gallbladder (GB-NENs) are a rare group of histologically heterogeneous tumors, and surgical resection of the primary tumor is the mainstream treatment at the moment. The current study aimed to establish and validate novel nomograms for patients with GB-NENs undergoing primary tumor resection to predict the 6-, 12-, and 18-month overall survival (OS) and cancer-specific survival (CSS).

The main purpose of this study is to analyze the clinicopathological features and prognosis factors of bile duct and ampullary neuroendocrine neoplasms (NENs).

Alterations in key-regulator genes of disease pathogenesis (BRAF, cKIT, CyclinD1) have been evaluated in patients with multiple primary melanoma (MPM).

Introduction: Several studies have reported that intraductal papillary mucinous neoplasms (IPMNs) of the pancreas are associated with extra-pancreatic malignancies. However, there have been no population-based studies evaluating the risk of second primary cancers (SPCs) in patients with pancreatic IPMN. Methods: The Surveillance, Epidemiology, and End Results (SEER) database was used to identify and characterize data from patients with IPMN of the pancreas. The standard incidence ratio (SIR) of this cancer was calculated by estimating the relative risk (RR). A multivariate Cox regression model was used to estimate hazards ratios (HRs) of death and associated 95% CIs. Results: Of 2,850 patients with IPMN of the pancreas, 104 patients (3.65%) developed 118 SPCs. The SIR for all SPCs combined was 1.22 (95% confidence interval [CI] = 1.01-1.46; P < 0.05). There was an elevated risk of site-specific SPCs in the small intestine (SIR = 8.68; 95% CI = 2.36-22.22), pancreas (SIR = 2.66; 95% CI = 1.15-5.25), urinary bladder (SIR = 2.02; 95% CI = 1.05-3.54), and eye and orbit (SIR = 13.47; 95% CI = 1.63-48.67) in patients with pancreas IPMN. In age subgrouping, people aged younger than 50 years had an increased risk of all-site SPC with an SIR of 6.44 (95% CI = 2.78-12.68). Cox regression modeling showed that advanced disease stage and a short latency period carried a higher risk of death in IPMN patients with SPC. Conclusions: Patients diagnosed with pancreatic IPMNs were at higher risk than the general population for developing a second primary malignancy. Meanwhile, advanced historic stage and short latency period were associated with an elevated HR in IPMN patients who develop an SPC.

Neoplastic and hyperplastic disorders that affect multiple endocrine tissues in a single individual are well described in humans but less so in domestic animals. Multiple endocrine neoplasia (MEN) in humans is a genetically determined syndrome characterized by the appearance of benign or malignant proliferations within two or more endocrine glands. The primary endocrine tumors that are characteristic of MEN arise from cells that share the capacity for amine precursor uptake and decarboxylation. Here we describe the case of a 22-year-old Thoroughbred mare that died during an unattended parturition and subsequently was presented for necropsy at the University of California, Davis, Veterinary Medical Teaching Hospital. A C-cell (medullary) thyroid adenoma, pheochromocytoma, and multicentric bilateral nodular hyperplasia of the adrenal medulla were present, findings that are remarkably similar to those of human MEN syndrome. Mortality during pregnancy in women with undiagnosed pheochromocytoma is high (approximately 50%), typically because of hypertension and/or hemorrhage associated with catecholamine release from the tumor. Similarly, the mare in this report died of hemorrhage subsequent to parturition. A retrospective evaluation of endocrine tumors in horses that underwent necropsy at the Veterinary Medical Teaching Hospital from 1987 to 1997 was undertaken to identify additional possible cases of MEN in horses. Data from this retrospective evaluation suggest that coexistence of hyperplasias and neoplasias of the thyroid and adrenal glands, similar to MEN syndrome of humans, also occurs with some frequency in the horse.

Patients who suffer from gastro-entero-pancreatic neuroendocrine neoplasms (GEP-NENs) often present with liver metastatic disease. The efficacy of primary tumor resection (PTR) for these patients remains controversial due to the relatively heterogeneous behavior of the primary tumor and the lack of clinical evidence. In this series, GEP-NEN patients with liver metastases (LM) were selected from the Surveillance, Epidemiology, and End Results database between 2010 and 2015. A logistic regression model was used to analyze variables that were associated with PTR. A Cox proportional hazards model was used to identify independent prognostic risk factors. In total, 1547 patients were enrolled in our study, including 897 patients who underwent PTR. Resection of the primary tumor was associated with prolonged survival in all patients (5-year overall survival (OS) rates: 57.0% vs 15.4%, P < .001), and improved 5-year OS rates were observed in patients with gastric, small intestinal, colorectal, and pancreatic subtypes (39.7%, 73.3%, 24.6%, and 59.7%, respectively). On the multivariate analysis, PTR was an independent prognostic factor of prolonged OS (HR = 0.48, 95% CI: 0.39-0.59, P < .001). Patients with a young age (≤60 years), small intestinal or colorectal NENs, a large primary tumor, lymph node (LN) metastases, and high tumor differentiation were more likely to undergo PTR. However, patients with colorectal NENs or a large primary tumor (≥4 cm) were at an increased risk of death independently in the PTR subgroup. The risk factors for OS also included old age, gastric tumor location, and poor differentiation. In conclusion, although PTR prolonged OS in all GEP-NEN patients presenting with LM, surgical recipients should be considered carefully. Age, primary tumor site, size, and differentiation might help surgeons identify patients who could benefit from PTR.

In recent years, a growing number of patients with multiple primary lung cancer (MPLC) are being diagnosed, and a subset of these patients is found to have a large number of lesions at the time of diagnosis, which are referred to as 'super MPLC'.

Purpose: The occurrence of parathyroid carcinoma (PC) and atypical parathyroid neoplasm (APN) in multiple endocrine neoplasia type 1 (MEN1) is rare. The present paper reports the cases of 3 MEN1-PC/APN patients at our center and discusses the prevalence in a Chinese MEN1 cohort. Methods: This report is a retrospective analysis of 153 MEN1-associated primary hyperparathyroidism (MEN1-HPT) patients at our center, which included 3 MEN1-associated PC/APN (MEN1-PC/APN) patients. The clinical manifestations, biochemical indices, pathological findings, and therapy have been summarized along with the report of the genetic testing of the 3 patients. Results: Of the 153 MEN1-HPT patients, 1 (0.7%) was histopathologically diagnosed with PC and 2 (1.3%) with APN. Three heterozygous mutations were identified in the 3 MEN1-PC/APN patients (c.917 T > G, c.431T > C, and c.549 G > C). The cumulative findings of 3 cases with 18 previously reported MEN1-PC/APN cases revealed that the mean serum calcium (Ca) level was 3.15 ± 0.44 mmol/L and the median parathyroid hormone (PTH) level was 327 pg/mL (214.1, 673.1), both of which were significantly higher as compared to the respective levels in non-PC/APN MEN1 patients at our center [Ca: 2.78 mmol/L [2.61, 2.88], PTH: 185.5 pg/mL [108.3, 297.0]; P = 0.0003, 0.0034, respectively]. Conclusion: MEN 1-PC/APN is a rare disease, with a prevalence of only 2.0% among the MEN1-HPT cohort at our center. The affected patients recorded higher serum Ca level and PTH levels than those with MEN1-associated benign tumors. However, the diagnosis of MEN1-PC/APN is based upon pathology most of the times.

BACKGROUND Various neoplasms, including neuroendocrine neoplasms (NENs), can arise from the presacral space. Most presacral lesions are detected due to symptoms arising from tumor growth. However, diagnosing small, asymptomatic presacral tumors is challenging because of their unique location. CASE REPORT A 63-year-old woman with chronic hepatitis C underwent follow-up after achieving a sustained virological response. Abdominal ultrasonography revealed multiple new hyperechoic masses in the liver. Physical and laboratory examinations, including tumor marker analysis, yielded unremarkable results. Computed tomography (CT) and magnetic resonance imaging (MRI) indicated metastatic liver tumors but failed to identify the primary site of these lesions. The hepatic mass was biopsied, leading to a diagnosis of grade 2 neuroendocrine tumor. 111In-pentetreotide somatostatin receptor scintigraphy revealed significant radiotracer accumulation in multiple hepatic masses, several bones, and a small presacral space lesion. Pathological examination of the presacral lesion confirmed a grade 2 neuroendocrine tumor, similar to the hepatic mass. Review of a CT scan performed 4 years earlier indicated a small cyst-like lesion in the presacral space suspected of being a developmental cyst; however, the presence of cystic components was not confirmed pathologically. The patient was diagnosed with a primary presacral neuroendocrine tumor, which might have originated from a developmental cyst, with multiple liver metastases. Chemotherapy with everolimus was initiated, and the clinical course has been uneventful. CONCLUSIONS We report a rare neuroendocrine tumor arising from the presacral space with multiple liver metastases. The presacral space should be examined when a NEN with an unknown primary site is found.

Few studies have investigated the risks of subsequent primary neoplasms after adolescent and young adult (AYA) cancer. We investigated the risks of specific subsequent primary neoplasms after each of 16 types of AYA cancer.

Pegylated liposomal doxorubicin (Peg-Dox) treatment resulted in a good outcome for patients with lymphoma and multiple myeloma, with reduced cardiotoxicity and an improved pharmacokinetic profile when compared to those of conventional doxorubicin. However, the use of Peg-Dox in myeloid neoplasms remains poorly studied. In this study, we first tested the role of Peg-Dox in the killing of myeloid cell lines and of primary myeloid leukemia cells. Then, a Peg-Dox-based protocol was used to treat patients with myeloid neoplasms. The results showed that the Peg-Dox and Peg-Dox-based protocols had a similar killing ability in myeloid cell lines and in primary myeloid leukemia cells compared to that of conventional doxorubicin. The complete remission rate was 87.5% and 100% for patients with refractory/relapsed acute myeloid leukemia and myelodysplastic syndrome with excess blasts, respectively, after treatment with Peg-Dox. All patients developed grade 3 or 4 hematological toxicity and recovered approximately 2 weeks after completing chemotherapy. No deaths or other severe complications were reported. Our results showed that Peg-Dox can be used in the treatment of myeloid neoplasms with high rates of complete remission and with mild complications.